Evil is a zinc finger gene that plays a regulatory role in hematopoiesis and a causative role in myeloid leukemia. We and others have shown that Evil has affects on cell proliferation, apoptosis, differentiation, and TGF? signaling. Using two different assays, we have shown that the ability of EVI1 to transform cells is strictly dependent on its ability to bind to DMA in a sequence-specific manner to a GACAAGATA-like motif. These findings imply that EVI1 binds to specific high-affinity sites in the genome and through this binding regulates a key set of target genes that are critical to its role in leukemogenesis. In a series of experiments using several complementary cell culture systems, we have identified some of these targets. They include genes involved in control of hematopoiesis (Gata2, Zfpm2/Fog2), apoptosis (Bcl2a1b, Dapk2), cell cycle (Ccnd2), and TGF? signaling (Skil). We hypothesize that EVI1 induces leukemia through the activation of cell proliferation and cell survival pathways, and that these effects are mediated through Gata2, a key downstream target of EVI1 and a critical regulator of hematopoiesis. To address this hypothesis, we propose three specific aims.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120313-05
Application #
8109836
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2007-09-13
Project End
2013-04-30
Budget Start
2011-08-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$260,810
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Glass, Carolyn; Wilson, Michael; Gonzalez, Ruby et al. (2014) The role of EVI1 in myeloid malignancies. Blood Cells Mol Dis 53:67-76
Zhang, Yi; Owens, Kristina; Hatem, Layla et al. (2013) Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia. Blood 122:2888-92
Glass, Carolyn; Wuertzer, Charles; Cui, Xiaohui et al. (2013) Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia. PLoS One 8:e67134
Bresnick, Emery H; Katsumura, Koichi R; Lee, Hsiang-Ying et al. (2012) Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies. Nucleic Acids Res 40:5819-31
Zhang, Yi; Stehling-Sun, Sandra; Lezon-Geyda, Kimberly et al. (2011) PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 118:3853-61